2.A.30.1.17
Solute carrier family 12 member 4 (Electroneutral potassium-chloride cotransporter 1, KCC1) (Erythroid K-Cl cotransporter 1) (hKCC1).  It is activated by cell swelling and may contribute to cell volume homeostasis as well as being involved in the regulation of basolateral Cl^- exit in NaCl absorbing epithelia. Isoform 4 has no transport activity. The kinase, WNK3, activates NKCC1/2 and NCC but inhibits the KCCs (Cruz-Rangel et al. 2011).  Liu et al. 2019 presented cryo-EM structures of human KCC1 in potassium chloride or sodium chloride at 2.9- to 3.5-Å resolution. KCC1 exists as a dimer, with both extracellular and transmembrane domains involved in dimerization. The structural and functional analyses, along with computational studies, reveal one potassium site and two chloride sites in KCC1, which are all required for the ion transport activity. The structure reveals an inward-facing conformation, with the extracellular gate occluded. The KCC1 structures allowed the authors to model a potential ion transport mechanism in KCCs and provide a blueprint for drug design (Liu et al. 2019). KCC1 bound with the VU0463271 inhibitor in an outward-open state has been solved (Zhao et al. 2022). In contrast to many other amino acid-polyamine-organocation transporter cousins, opening the KCC1 extracellular ion permeation path does not involve hinge-bending motions of TMS 1 and TMS6 half-helices. Instead, rocking of TMS3 and TMS8, together with displacements of TMS4, TMS9, and a conserved intracellular loop 1 helix, underlie alternate opening and closing of extracellular and cytoplasmic vestibules. KCC1 exists in one of two distinct dimeric states via different intersubunit interfaces (Zhao et al. 2022).